Synthesis and antibacterial activity of 4" or 6"-alkanoylamino derivatives of arbekacin

Arbekacin, an aminoglycoside antibiotic, is an important drug because it shows a potent efficacy against methicillin-resistant Staphylococcus aureus. However, resistance to arbekacin, which is caused mainly by the bifunctional aminoglycoside-modifying enzyme, has been observed, becoming a serious problem in medical practice. To create new arbekacin derivatives active against resistant bacteria, we modified the C-4 '' and 6 '' positions of its 3-aminosugar portion. Regioselective amination of the 6 ''-position gave 6 ''-amino-6 ''-deoxyarbekacin (1), and it was converted to a variety of 6 ''-N-alkanoyl derivatives (6a-z). Furthermore, regioselective modifications of the 4 ''-hydroxyl group were performed to give 4 ''-deoxy-4 ''-epiaminoarbekacin (2) and its 4 ''-N-alkanoyl derivatives (12 and 13). Their antibacterial activity against S. aureus, including arbekacin-resistant bacteria, was evaluated. It was observed that 6 ''-amino-6 ''-N-[(S)-4-amino-2-hydroxybutyryl]-6 ''-deoxyarbekacin (6o) showed excellent antibacterial activity, even better than arbekacin.